Substituted anilide esters of PGA

ABSTRACT

Substituted anilide esters of PGA1, 15-alkyl-PGA1, and 15(R)-15-alkyl-PGA1, and their racemic forms, and processes for producing them are disclosed. The products are useful for the same pharmacological and medical purposes as PGA1, 15-alkyl-PGA1, and 15(R)-15-alkyl-PGA1, and are also useful as a means for obtaining highly purified PGA1, 15-alkyl-PGA1, and 15(R)-15-alkyl-PGA1 products.

BACKGROUND OF THE INVENTION

This invention relates to novel ester derivatives of prostaglandin A₁(hereinafter identified as "PGA₁ "), 15-alkyl-PGA₁, 15(R)-15-alkyl-PGA₁,and their racemic forms, and to processes for producing them.

PGA₁ is represented by the formula: ##SPC1##

A systematic name for PGA₁ is7-{2β-[(3S)-3-hydroxy-trans-1-octenyl]-5-oxo-1.sub.α-cyclo-3-pentenyl}heptanoicacid. PGA₁ is known to be useful for a variety of pharmacological andmedical purposes, for example to reduce and control excessive gastricsecretion, to increase the flow of blood in the mammalian kidney as incases of renal dysfunction, to control spasm and facilitate breathing inasthmatic conditions, and as a hypotensive agent to reduce bloodpressure in mammals, including humans. See Bergstrom et al., Pharmacol.Rev. 20, 1 (1968) and references cited therein. As to racemic PGA₁, seefor example P. W. Ramwell, Nature 221, 1251 (1969).

The 15-alkyl-PGA₁ analog and its 15(R) epimer are represented by theformula ##SPC2##

Wherein Y' is ##EQU1## following the usual convention wherein brokenline attachment of hydroxy to the side chain at carbon 15 indicates thenatural or "S" configuration and solid line attachment of hydroxyindicates the epi or "R" configuration. See for example Nugteren et al.,Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964). The15-alkyl- and 15(R)-15-alkyl-PGA₁ analogs in their optically active andracemic forms are known. See for example Belg. Pat. No. 772,584, DerwentFarmdoc No. 19694T. These analogs are also useful for theabove-described pharmacological purposes.

Esters of the above compounds are known, wherein the hydrogen atom ofthe carboxyl group is replaced by a hydrocarbyl or substitutedhydrocarbyl group. Among these is the methyl ester of PGA₁ (J. P. Lee etal., Biochem. J. 105, 1251 (1967)).

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel ester derivatives ofprostaglandin PGA₁, 15-alkyl-PGA₁, 15(R)-15-alkyl-PGA₁, and theirracemic forms. It is a further purpose to provide such esters derivedfrom substituted phenols and naphthols. It is a further purpose toprovide such esters in a free-flowing crystalline form. It is still afurther purpose to provide novel processes for preparing these esters.

The presently described esters include compounds represented by thegeneric formula: ##SPC3##

wherein Z is the substituted phenyl or naphthyl group as definedimmediately below, and Y is ##EQU2## i.e. esters of PGA₁,15-methyl-PGA₁, 15(R)-15-methyl-PGA₁, 15-ethyl-PGA₁, and15(R)-15-ethyl-PGA₁ ; and also the racemic compounds represented by eachrespective formula and the mirror image thereof; Z being represented by##SPC4##

For example, PGA₁, p-acetamidophenyl ester, is represented by formulaIII when Y is ##EQU3## and Z is A, i.e. ##SPC5##

and is conveniently identified herein as the PGA₁ ester of formulaIII-A. Racemic compounds are designated by the prefix "racemic" or "dl";when that prefix is absent, the intent is to designate an opticallyactive compound. Racemic 15-methyl-PGA₁, p-benzamidophenyl ester,corresponds to formula III wherein Y is ##EQU4## and Z is B, i.e.##SPC6##

including of course not only the optically active isomer represented byformula III but also its mirror image.

The novel formula-III compounds and corresponding racemic compounds ofthis invention are each useful for the same purposes as described abovefor PGA₁ and are used for those purposes in the same manner known in theart, including oral, sublingual, buccal, rectal, intravaginal,intrauterine, or topical administration.

For many applications these novel prostaglandin esters which I haveobtained from certain specific phenols and naphthols have advantagesover the corresponding known prostaglandin compounds. Thus, thesesubstituted phenyl and naphthyl esters are surprisingly stable compoundshaving outstanding shelf-life and thermal stability. In contrast to theacid form of these prostaglandins, these esters are not subject todecomposition either by elimination of water, or epimerization, orisomerization. Thus these compounds have improved stability either insolid, liquid, or solution form. In oral administration these estershave shown surprisingly greater efficacy than the corresponding freeacids or lower alkyl esters, whether because of longer duration ofbiological activity or because of improved lipophilicity and absorptionis not certain. These esters offer a further advantage in that they havelow solubility in water and the body fluids and are therefore retainedlonger at the site of administration.

A particularly outstanding advantage of many of these substituted phenyland naphthyl esters is that they are obtained in free-flowingcrystalline form, generally of moderately high melting point, in therange 90°-180° C. This form is especially desirable for ease ofhandling, administering, and purifying. These crystals are highlystable, for example showing practically no decomposition at acceleratedstorage tests at 65° C., in comparison with liquid alkyl esters or thefree acids. This quality is advantageous because the compound does notlose its potency and does not become contaminated with decompositionproducts.

These crystalline esters also provide a means of purifying PGA₁,15-methyl-PGA₁, 15(R)-15methyl-PGA₁, 15-ethyl-PGA₁, or15(R)-15-ethyl-PGA₁, which are first converted to one of these esters,recrystallized until pure, and then recovered as the free acid. Onemethod of recovering the free acid is by enzymatic hydrolysis of theester, for example with a lipase. See German Pat. No. 2,242,792, DerwentFarmdoc No. 23047U.

To obtain the optimum combination of stability, duration of biologicalactivity, lipophilicity, solubility, and crystallinity, certaincompounds within the scope of formula III are preferred.

One preference is that Z is limited to either ##SPC7##

Another preference is that Z is further limited to ##SPC8##

wherein R₁ is ##SPC9##

wherein R₂ is ##SPC10##

Another preference is that Z is limited to ##SPC11##

Another preference is that Z is limited to ##SPC12##

wherein R₃ is ##SPC13##

wherein R₄ is ##SPC14##

Especially preferred are those compounds which are in free-flowingcrystalline form, for example:

p-benzamidophenyl ester of PGA₁

p-ureidophenyl ester of PGA₁

2-naphthyl ester of PGA₁

The substituted phenyl and naphthyl esters of PGA₁, 15-alkyl-PGA₁ and15(R)-15-alkyl-PGA₁, encompassed by formula III wherein Z is defined byester groups A through Y are produced by the reactions and proceduresdescribed and exemplified hereinafter. For convenience, the aboveprostaglandin or prostaglandin analog is referred to as "the PGcompound". The term "phenol" is used in a generic sense, including bothphenols and naphthols.

Various methods are available for preparing these esters, differing asto yield and purity of product. Thus, by one method, the PG compound isconverted to a tertiary amine salt, reacted with pivaloyl halide to givethe mixed acid anhydride and then reacted with the phenol. Alternately,instead of pivaloyl halide, an alkyl or phenylsulfonyl halide is used,such as p-toluenesulfonyl chloride. See for example Belgian Pat. Nos.775,106 and 776,294, Derwent Farmdoc Nos. 33705T and 39011T.

Still another method is by the use of the coupling reagent,dicyclohexylcarbodiimide. See Fieser et al., "Reagents for OrganicSynthesis", pp. 231-236, John Wiley and Sons, Inc., New York (1967). ThePG compound is contacted with one to ten molar equivalents of the phenolin the presence of 2-10 molar equivalents of dicyclohexylcarbodiimide inpyridine as a solvent.

The preferred novel process for the preparation of these esters,however, comprises the steps (1) forming a mixed anhydride with the PGcompound and isobutylchloroformate in the presence of amine tertiarymaine and (2) reacting the anhydride with an appropriate phenol ornaphthol.

The mixed anhydride is represented by the formula: ##SPC15##

for the optically active PG compounds, Y having the same definition asabove.

The anhydride is formed readily at temperatures in the range -40° to+60° C., preferably at -10° to +10° C. so that the rate is reasonablyfast and yet side reactions are minimized. The isobutylchloroformatereagent is preferably used in excess, for example 1.2 molar equivalentsup to 4.0 per mole of the PG compound. The reaction is preferably donein a solvent and for this purpose acetone is preferred, although otherrelatively non-polar solvents are used such as acetonitrile,dichloromethane, and chloroform. The reaction is run in the presence ofa tertiary amine, for example triethylamine, and the co-formed aminehydrochloride usually crystallizes out, but need not be removed for thenext step.

The anhydride is usually not isolated but is reacted directly insolution with the phenol, preferably in the presence of a tertiary aminesuch as pyridine.

The phenol is preferably used in equivalent amounts or in excess toinsure that all of the mixed anhydride is converted to ester. Excessphenol is separated from the product by methods described herein orknown in the art, for example by crystallization. The tertiary amine isnot only a basic catalyst for the esterification but also a convenientsolvent. Other examples of tertiary amines useful for this purposeinclude N-methylmorpholine, triethylamine, diisopropylethylamine, anddimethylaniline. Although they may be used, 2-methylpyridine andquinoline result in a slow reaction. A highly hindered amine such as2,6-dimethyllutidine is not useful because of the slowness of thereaction.

The reaction with the anhydride proceeds smoothly at room temperature(about 20° to 30° C.) and can be followed in the conventional mannerwith thin layer chromatography (TLC), usually being found completewithin 1-4 hours.

The reaction mixture is worked up to yield the ester following methodsknown in the art, and the product is purified, for example by silica gelchromatography.

Solid esters are converted to a free-flowing crystalline form oncrystallization from a variety of solvents, including ethyl acetate,tetrahydrofuran, methanol, and acetone, by cooling or evaporating asaturated solution of the ester in the solvent or by adding a misciblenon-solvent such as diethyl ether, hexane, or water. The crystals arethen collected by conventional techniques, e.g. filtration orcentrifugation, washed with a small amount of solvent, and dried underreduced pressure. They may also be dried in a current of warm nitrogenor argon, or by warming to about 75° C. Although the crystals arenormally pure enough for many applications, they may be recrystallizedby the same general techniques to achieve improved purity after eachrecrystallization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples.

All temperatures are in degrees centigrade.

Silica gel chromatography, as used herein, is understood to includechromatography on a column packed with silica gel, elution, collectionof fractions, and combination of those fractions shown by thin layerchromatography (TLC) to contain the desired product free of startingmaterial and impurities.

"TLC", herein, refers to thin layer chromatography.

PREPARATION 1 p-Benzamidophenol

A solution of p-hydroxyaniline (20 g.) in 200 ml. pyridine is treatedwith benzoic anhydride (20 g.). After 4 hr. at about 25° C., the mixtureis concentrated under reduced pressure and the residue is taken up in200 ml. of hot methanol and reprecipitated with 300 ml. of water. Theproduct is recrystallized from hot acetonitrile as white crystals, 8.5g., m.p. 218.0°-218.5° C.

PREPARATION 2 p-(p-Acetamidobenzamido)phenol

A solution of p-acetamidobenzoic acid (12.5 g.) in 250 ml. oftetrahydrofuran is treated with triethylamine (11.1 ml.). The mixture isthen treated with isobutylchloroformate (10.4 ml.) and, after 5 min. atabout 25° C., with p-aminophenol (13.3 g.) in 80 ml. of dry pyridine.After 40 min. the crude product is obtained by addition of 2 liters ofwater. The product is recrystallized from 500 ml. of hot methanol bydilution with 300 ml. of water as white crystals, 5.9 g., m.p.275.0°-277.0° C.

EXAMPLE 1 PGA₁, p-Acetamidophenyl Ester (Formula III-A)

A solution of PGA₁ (0.506 g.) and triethylamine (0.250 ml.) in 20 ml. ofacetone is treated at -10° C. with isobutylchloroformate (0.236 ml.)whereupon triethylamine hydrochloride is precipitated. After 5 min. themixture is treated with p-acetamidophenol (0.453 g.) in 5 ml. ofpyridine for 3 hr. at about 25° C. The solvent is removed under reducedpressure and the residue is dissolved in ethyl acetate and washed withaqueous citric acid (2%) and water. The organic phase is dried oversodium sulfate, concentrated, and subjected to silica gelchromatography, eluting with chloroform-acetonitrile (7:3) containing 1%water, followed by chloroform-acetonitrile (1:4). The residue obtainedby concentration of selected fractions, an oil, is the title compound,0.539 g., having R_(f) 0.4 (TLC on silica gel in chloroform-acetonitrile(7:3)).

EXAMPLE 2 p-Benzamidophenyl Ester of PGA₁ (Formula III-B)

Following the procedure of EXample 1 but using 0.510 g. of PQA.sub. 1,0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and0.484 g. of p-benzamidophenol (Preparation 1), there is obtained a cruderesidue. This residue is subjected to silica gel chromatography, elutingwith chloroform-acetonitrile (85:15). The residue obtained byconcentration of selected fractions, 0.505 g., is crystallized fromethyl acetate diluted with 2.5 volumes of hexane as the title compound,white free-flowing crystals, m.p. 96.8°-98.3° C., having R_(f) 0.6 (TLCon silica gel in chloroform-acetonitrile (4:1).

EXAMPLE 3 p-Hydroxyphenylurea Ester of PGA₁, (Formula III-E)

Following the procedure of Example 1 but using 0.506 g. of PGA₁, 0.250ml. of triethylamine, 0.236 ml. of isobutylchloroformate, and 0.456 g.of p-hydroxyphenylurea, there is obtained a crude residue. This residueis subjected to silica gel chromatography, eluting with ethylacetate-acetonitrile-water (94:5:1). The residue obtained byconcentration of selected fractions, 0.646 g., is crystallized fromethyl acetate as the tital compound, white free-flowing crystals, m.p.96.3°-98.3° C., having R_(f) 0.4 (TLC on silica gel in ethylacetate-acetonitrile (95:5)).

EXAMPLE 4 p-Acetylphenyl Ester of PGA₁ (Formula III-L)

Following the procedure of Example 1 but using 0.508 g. of PGA₁, 0.254ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.309 g.of p-hydroxyacetophenone, there is obtained a crude residue. Thisresidue is subjected to silica gel chromatography, eluting with ethylacetate-hexane (2:3), followed by ethyl acetate-hexane (7:3). Theresidue obtained by concentration of selected fractions, 0.500 g., anoil, is the title compound, having R_(f) 0.4 (TLC on silica gel in ethylacetate-hexane (1:1)).

EXAMPLE 5 p-Carbamoylphenyl Ester of PGA₁ (Formula III-N).

Following the procedure of Example 1 but using 0.506 g. of PGA₁ 0.250ml. of triethylamine, 0.236 ml. of isobutylchloroformate, and 0.412 g.of p-hydroxybenzamide there is obtained a crude residue. This residue issubjected to silica gel chromatography, eluting withchloroform-acetonitrile (6:4). The residue obtained by concentration ofselected fractions, 0.260 g., an oil, as the title compound, havingR_(f) 0.5 (TLC on silica gel in chloroform-acetonitrile (3:2)).

EXAMPLE 6 2-Naphthyl Ester of PGA₁ (Formula III-X)

Following the procedure of Example 1 but using 0.506 g. of PGA₁, 0.254ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.327 g.of β-naphthol, there is obtained a crude residue. This residue issubjected to silica gel chromatography, eluting with ethylacetate-hexane (2:3) followed by ethyl acetate-hexane (7:3). The residueobtained by concentration of selected fractions, 0.45 g., iscrystallized from ethyl acetate diluted with two volumes of hexane asthe title compound, white free-flowing crystals, m.p. 49.0°-50.0° C.,having R_(f) 0.5 (TLC on silica gel in ethyl acetate-hexane (1:1)).

Following the procedures of Examples 1-6 but employing the racemic formsof the PG compounds, there are obtained the corresponding esters ofracemic PG compounds.

EXAMPLES 7-76

The substituted phenyl and naphthyl esters of PGA₁, 15-methyl-PGA₁, and15(R)-15-methyl-PGA₁ of Tables I-III below are obtained following theprocedures of Example 1, wherein the prostaglandin compound is reactedin the presence of triethylamine and isobutylchloroformate with theappropriate hydroxy phenyl or naphthyl compound, listed in the Table.These phenols or naphthols are readily available or prepared by methodsdescribed herein or known in the art. The crude products, obtained byconcentration under reduced pressure, are purified by means describedherein or known in the art, including partitioning, solvent extraction,washing, silica gel chromatography, trituration, or crystallization.

Following the procedures of Examples 7-76 but employing the racemicforms of the PG compounds, there are obtained the corresponding estersof the racemic PG compounds.

                  TABLE 1                                                         ______________________________________                                        Esters of PGA.sub.1                                                                Hydroxy Phenyl or      Product PGA.sub.1                                 Ex.  Naphthyl Compound      Ester of formula:                                 ______________________________________                                         7   p-acetamidophenol      III-A                                              8   p-(p-acetamidobenzamido)phenol                                                                       III-C                                              9   p-(p-benzamidobenzamido)phenol                                                                       III-D                                             10   p-hydroxy-1,3-diphenylurea                                                                           III-F                                             11   p-phenylphenol         III-G                                             12   p-tritylphenol         III-H                                             13   N-acetyl-L-tyrosinamide                                                                              III-I                                             14   N-benzoyl-L-tyrosinamide                                                                             III-J                                             15   p-hydroxybenzaldehyde semicarbazone                                                                  III-K                                             16   p-hydroxybenzophenone  III-M                                             17   o-hydroxybenzamide     III-O                                             18   N-(p-tritylphenyl)-p-hydroxybenzamide-                                                               III-P                                             19   p-hydroxybenzoic acid, methyl ester                                                                  III-Q                                             20   hydroquinone benzoate  III-R                                             21   hydroquinone, p-acetamidobenzoic                                              acid ester             III-S                                             22   2,4-diacetamidophenol  III-T                                             23   1-acetamido-4-hydroxnaphthalene                                                                      III-U                                             24   1-benzamido-4-hydroxynaphthalene                                                                     III-V                                             25   1-hydroxy-4-ureidonaphthalene                                                                        III-W -26 1-hydroxy-5-naphthalenesulfonamide I                                II-Y                                              ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Esters of 15-Methyl-PGA.sub.1                                                                             Product                                                Hydroxy Phenyl or      15-Methyl-PGA.sub.1                               Ex.  Naphthyl Compound      Ester of formula                                  ______________________________________                                        27   p-acetamidophenol      III-A                                             28   p-benzamidophenol      III-B                                             29   p-(p-acetamidobenzamido)phenol                                                                       III-C                                             30   p-(p-benzamidobenzamido)phenol                                                                       III-D                                             31   p-hydroxyphenylurea    III-E                                             32   p-hydroxy-1,3-diphenylurea                                                                           III-F                                             33   p-phenylphenol         III-G                                             34   p-tritylphenol         III-H                                             35   N-acetyl-L-tyrosinamide                                                                              III-I                                             36   N-benzoyl-L-tyrosinamide                                                                             III-J                                             37   p-hydroxybenzaldehyde semicarbazone                                                                  III-K                                             38   p-hydroxacetophenone   III-L                                             39   p-hydroxybenzophenone  III-M                                             40   p-hydroxybenzamide     III-N                                             41   o-hydroxybenzamide     III-O                                             42   N-(p-tritylphenyl)-p-hydroxybenzamide                                                                III-P                                             43   p-hydroxybenzoic acid, methyl ester                                                                  III-Q                                             44   hydroquinone benzoate  III-R                                             45   hydroquinone, p-acetamidobenzoic                                                                     III-S                                                  acid ester                                                               46   2,4-diacetamidophenol  III-T                                             47   1-acetamido-4-hydroxynaphthalene                                                                     III-U                                             48   1-benzamido-4-hydroxynaphthalene                                                                     III-V                                             49   1-hydroxy-4-ureidonaphthalene                                                                        III-W                                             50   2-naphthol             III-X                                             51   1-hydroxy-5-naphthalenesulfonamide                                                                   III-Y                                             ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Esters of 15(R)-15-Methyl-PGA.sub.1                                                                       Product 15(R)-15-                                      Hydroxy Phenyl or      Methyl-PGA.sub.1                                  Ex.  Naphthyl Compound      Ester of formula:                                 ______________________________________                                        52   p-acetamidophenol      III-A                                             53   p-benzamidophenol      III-B                                             54   p-(p-acetamidobenzamido)phenol                                                                       III-C                                             55   p-(p-benzamido)phenol  III-D -56 p-hydroxyphenlurea III-E                57   p-hydroxy-1,3-diphenylurea                                                                           III-F                                             58   p-phenylphenol         III-G                                             59   p-tritylphenol         III-H                                             60   N-acetyl-L-tyrosinamide                                                                              III-I                                             61   N-benzoyl-L-tyrosinamide                                                                             III-J                                             62   p-hydroxybenzaldehyde semicarbazone                                                                  III-K                                             63   p-hydroxyacetophenone  III-L                                             64   p-hydroxybenzophenone  III-M                                             65   p-hydroxybenzamide     III-N                                             66   o-hydroxybenzamide     III-O                                             67   N-(p-tritylphenyl)-p-hydroxybenzamide                                                                III-P                                             68   p-hydroxybenzoic acid, methyl ester                                                                  III-Q                                             69   hydroquinone benzoate  III-R                                             70   hydroquinone, p-acetamidobenzoic                                                                     III-S                                                  acid ester                                                               71   2,4-diacetamidophenol  III-T                                             72   1-acetamido-4-hydroxynaphthalene                                                                     III-U                                             73   1-benzamido-4-hydroxynaphthalene                                                                     III-V                                             74   1-hydroxy-4-ureidonaphthalene                                                                        III-W                                             75   2-naphthol             III-X                                             76   1-hydroxy-5-naphthalenesulfonamide                                                                   III-Y                                             ______________________________________                                    

What is claimed is:
 1. An optically active compound of the formula:##SPC16##or a racemic compound of that formula and the mirror imagethereof, wherein Z is ##SPC17## wherein R₁ is ##SPC18## wherein R₂ is##SPC19## and wherein Y is ##EQU5##
 2. The ester ofp-(p-acetamidobenzamido)phenol and PGA₁, a compound according toclaim
 1. 3. The ester of 1-acetamido-4-hydroxynaphthalene and PGA₁, acompound according to claim
 1. 4. The ester of1-hydroxy-4-ureidonaphthalene and PGA₁, a compound according to claim 1.5. The ester of p-(p-acetamidobenzamido)phenol and 15-methyl-PGA₁, acompound according to claim
 1. 6. The ester of1-hydroxy-4-ureidonaphthalene and 15-methyl-PGA₁, a compound accordingto claim
 1. 7. The ester of p-(p-acetamidobenzamido)phenol and15(R)-15-methyl-PGA₁, a compound according to claim
 1. 8. The ester ofp-acetamidophenol and PGA₁, a compound according to claim
 1. 9. Theester of p-benzamidophenol and PGA₁, a compound according to claim 1.10. The ester of p-hydroxyphenylurea and PGA₁, a compound according toclaim
 1. 11. Free-flowing crystals of a compound of the formula:##SPC20##wherein E is ##SPC21##